N-phenylpropylene substituted tetrahydro-isoquinolines

ABSTRACT

NOVEL TETRAHYDRO-ISOQUINOLINES BEARING IN THE 2-POSITION A SUBSTITUTED PHENYLPROPYLENE GROUP AND PROCESSES FOR THE PREPARATION THEREOF ARE DISCLOSED. THESE NOVEL DERIVATIVES ARE USEFUL AS ANALGESIC AND ANTITUSSUVE AGENTS AND TO REDUCE INTESTINAL MOTILITY.

3,812,133 N-PHENYLPROPYLENE SUBSTITUTED TETRAHYDRO-ISOQUINOLINES John Mervyn Osbond, Hatfield, and Graham Alwyn Fothergill, Knebworth, England, assignors to Holfmann- La Roche Inc., Nutley, NJ. No Drawing. Filed Nov. 22, 1971, Ser. No. 203,100 Int. Cl. C07d 35/28 U.S. Cl. 260-289 R 9 Claims ABSTRACT OF THE DISCLOSURE Novel tetrahydro-isoquinolines bearing in the 2-position a substituted phenylpropylene group and processes for the preparation thereof are disclosed. These novel derivatives are useful as analgesic and antitussive agents and to reduce intestinal motility.

DETAILED DESCRIPTION OF THE INVENTION HaC-O q R H304, tween-hrwonQ-m R1 cm (I) wherein R is lower alkyl or cycloalkyl; R is hydrogen or lower alkanoyl; R and R each individually represent lower alkyl or R and R taken together signify trimethylene, tetramethylene or a butadiene-(l,3-ylenegroup and the pharmaceutically acceptable acid addition salts thereof.

As used herein, the term lower alkyl refers to straight and branched chain hydrocarbon groups containing from 1 to 7, preferably from 1-4, carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like. The term cycloalkyl refers to groups containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclo'butyl, cyclopentyl and cyclohexyl. The term lower alkanoy includes the acryl residue of lower alkanoic acids containing up to 6 carbon atoms such as acetyl, propionyl, and butyryl.

In a preferred aspect of the present invention, when the R substituent is a lower alkyl group, ethyl, isobutyl and hexyl are preferred. When the R and/or R substituent is lower alkyl, methyl is preferred. When the R substituent is cycloalkyl, cyclohexyl is preferred and when the R substituent is lower alkanoyl, acetyl is preferred.

United States Patent 3,812,133 Patented May 21, 1974 ice A preferred class of compounds falling within the scope of formula I above are those wherein R and R each represent lower alkyl, i.e. compounds of the formula H: C 0 lower alkyl lower alkyl CH; (Ia) wherein R and R are as described above and the pharmaceutically acceptable acid addition salts thereof.

The most preferred of the compounds of formula I above are:

or an acid addition salt thereof, with formaldehyde and a ketone of the general formula 3 (III) wherein R, R and R are as described above.

This Mannich reaction yields an acid addition salt of a compound of the formula wherein R, R and R are as described above.

The Mannich reaction can be carried out using either an acid addition salt of a compound of formula II, formaldehyde and a ketone of formula III or a compound of formula II, formaldehyde and a ketone of formula III in the presence of an acid. Suitable acids include the hydrohalic acids, especially hydrochloric acid, sulfuric acid and strong organic acids such as trichloroacetic acid. It is advantageous to use more than one mole of acid per mole of a compound of formula II. The Mannich reaction can conveniently be carried out by heating the reactants together in an inert organic solvent such as an alkanol containing from 1 to 4 carbon atoms, i.e. methanol or ethanol, for a period of up to about 72 hours. In certain circumstances, it may be advantageous to add further quantities of formaldehyde to the reaction mixture during the course of the reaction (e.g. at about 24 hours and about 48 hours when the reaction is carried out for a period of 72 hours). The formaldehyde is suitably provided in the form of a polymer thereof such as paraformaldehyde. In a preferred embodiment, this reaction is carried out using an acid addition salt, especially a hydrohalide salt such as the hydrochloride, of a compound of formula II and, in this case, it may be advisable to include in the reaction mixture a small amount of the acid corresponding to the acid addition salt used.

The compound of formula IV, obtained as described above, is then reduced either catalytically or by treatment with an alkali-metal aluminum hydride or alkali-metal borohydride. The catalytic reduction is preferably carried out in an alkanol containing from 1 to 4 carbon atoms such as methanol or ethanol using hydrogen in the presence of a platinum or palladium catalyst (e.g. palladiumon-carbon or platinum oxide). This catalytic reduction can conveniently be carried out at room temperature and at atmospheric pressure. The reduction using an alkali-metal aluminum hydride or alkali-metal borohydride can suitably be carried out at room temperature or at a temperature below room temperature in an inert organic solvent. Where an alkali-metal aluminum hydride is used suitable solvents include anhydrous ethers such as diethyl ether and tetrahydrofuran and where an alkali-metal borohydride is used suitable solvents include alkanols containing from 1 to 4 carbon atoms such as methanol and ethanol or dioxane or an aqueous solution thereof. Lithium aluminum hydride is the preferred alkali-metal aluminum hydride and sodium borohydride is the preferred alkali-metal borohydride.

The reduction of a compound of formula IV yields the corresponding compound of formula I wherein R, signifies hydrogen, or an acid addition salt thereof, depending upon the reduction system employed. Thus, the reduction of a compound of formula IV results in a compound of the formula moo R wherein R, R and R are as described above or an acid addition salt thereof.

The compounds of formula I above wherein R signifies a lower alkanoyl group can be prepared by the introduction of this group into the corresponding compound of formula Ib above. The lower alkanoylation can be carried using conventional techniques, for example, using a lower alkanoyl halide such as acetyl chloride or propionyl bromide or an anhydride of an alkanoic acid containing up to 6 carbon atoms such as acetic anhydride. According to a preferred embodiment, the lower-alkanoylation is carried out using an anhydride of an alkanoic acid containing up to 6 carbon atoms in the presence of a catalytic amount of a strong acid such as perchloric acid.

Preferred embodiments of the foregoing process comprise reacting 6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride with 1,2-dimethyl-4-isocaproylbenzene, 1,2-dimethyl-4-octanoyl-benzene, 4-(2-cyclohexyl-acetyl)-l,2-dimethyl-benzene or 2-butyry1-5,6,7,8-tetrahydro-naphthalene and reducing the reaction product and, if desired, in the case of the first three embodiments acetylating the reduction product.

The compounds of formula II above and their acid addition salts are known and can be prepared, for example, by reducing 1-methyl-6,7-dimethoxy-3,4-dihydro-isoquinoline and, where required, converting the product into an acid addition salt.

The ketone starting materials of formula III above are also known and can be prepared, for example, by reacting a compound of the genreal formula wherein R and R are as described above with a compound of the general formula wherein R is as described above under the conditions employed for a Friedel-Crafts reaction. A preferred class of ketone starting materials include those compounds of formula III in which R, and R each represent lower alkyl.

The compounds of formula I can be converted into their pharmaceutically acceptable acid addition salts by treatment with pharmaceutically acceptable inorganic acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid and phosphoric acid and with pharmaceutically acceptable organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid. Where an acid addition salt of a compound of formula I is obtained according to the process of this invention, such salt can be converted into the free base by treatment with alkali.

It will be appreciated that the isoquinoline derivatives provided by the invention can occur in racemic and optically active form and that the invention includes within its scope both the racemic and the optically active forms. A racemate can, if desired, be separated into its optical isomers in accordance with conventional methods, for example, by fractional crystallization of its salts formed with optically active acids. The optical isomers can, however, also be obtained by using an optically active starting material of formula II or by resolving an appropriate intermediate obtained during the process.

The compounds of formula I above and the pharmaceutically acceptable acid addition salts thereof can be used as medicaments in the form of pharmaceutical preparation which contain them in association with a compatible pharmaceutical carrier. The carrier material may be an organic or inorganic inert carrier material which is suitable for enteral (e.g. oral) or parenteral administration. Examples of such carrier materials are water, gelatin, starch, talc, magnesium stearate, lactose and polyalkylene glycols. The pharmaceutical preparations can be made up in solid form (e.g. tablets, dragees and capsules) or in liquid form (e.g. solutions, suspensions and emulsions).

The compounds of formula I above and their pharmaceutically acceptable acid addition salts are useful as analgesic and anti-tussi've agents. In addition, the compounds of the present invention substantially reduce intestinal motility and accordingly these compounds and their pharmaceutically acceptable salts may be used as agents for alleviating diarrhaea.

The aforementioned analgesic and intestinal motility activities of the tetrahydro-isoquinoline derivatives of the present invention are shown in Table I.

6 on each occasion) being added after 24 hours and 48 hours. After cooling, the resulting mixture was concentrated under reduced pressure. The residual gum was TABLE 1 MgJkg. (per es) in mice Compounds of formula I wherein: Intestinal motility:

standard R R1 Ra Ra Analgesia: efiective signifiesslgnifiessignifiessignifles- D PD dose CHzOH(CHa)a H -CHs CH.\; 355 4.5 0.8 CHTCH (CH OOCH: CH3 CHa 325 12. 5 3. 3 '-(CH2)sCHs CHa CHs 500 1. 5 1. 1 -(CH:)OH3 COCH; CH: -CH3 1, 600 6.0 0. 45 -CH2CHs H (GH2)4 400 4.5 2.5

O H CHa CH5 000 9. 1. 9 Q COCHs CHa -CH:: 400 6.0 0.85

The test procedures followed to compile the above data as to analgesic and intestinal motility activity can be described as follows:

(1) Analgesic test in mice (writhing test) Groups of five mice are treated orally with the test compound 20 minutes before administration of the writhing agent (2-phenyl-1,4-benzoquinone). The number of writhes is counted in each group of five mice over a period of to 10 minutes after administration of the writhing agent. The results are reported as PD- i.e. the dose in mg./kg. required to produce a 50% reduction of writhing.

(2) Inhibition of intestinal motility The charcoal meal test of Macht and Barba-Gose (J. Amer. Pharm., Ass., Sci. ed. 1931, 20, 558) with modifications by Green (Brit. J. Pharmacol, 1959, 14, 26) was used. The animals are fed on milk with 3 percent glucose for eighteen hours before the experiment. The test meal, a smooth suspension of charcoal, wheat flour and water (122:6), was 0.3 ml. of suspension given orally. The mice were killed minutes later, the gut removed and the distance the charcoal had travelled measured from the pyloric end of the stomach. The results are expressed as percentages of the distance travelled in the controls and the dose of compound producing a percent inhibition is determined.

The following examples illustrate the process provided by the invention:

EXAMPLE 1 (A) The preparation of the starting material 134.5 g. of isocapropyl chloride were added dropwise at room temperature to a vigorously stirred suspension of 133.5 g. of aluminum chloride in 1200 ml. of dry dichloromethane. The resulting mixture was stirred at room temperature for a further 2 hours, then cooled in ice-water, treated dropwise over 0.5 hour with 106 g. of ortho-xylene, stirred at room temperature for 3 hours, allowed to stand at room temperature overnight, and poured on to ice-cold hydrochloric acid. The lower organic layer was separated olf, washed successively with water, dilute aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The oily residue was distilled to give 119.7 g. of 1,2-dimethyl-4-isocaproylbenzene as a pale-yellow oil of boiling point 160-166 C./ 15 mm.

'(B) The process A mixture of 61.2 g. of 1,2-dimethyl-4-isocaproylbenzene, 73.2 g. of 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 13.5 g. of paraformaldehyde, 0.5 ml. of concentrated hydrochloric acid and 150 ml. of methylated spirits was heated under reflux for 72 hours, further quantities of paraformaldehyde (13.5 g.

triturated with diethyl ether to give a pale-yellow semicrystalline solid which was filtered 01f, washed well with water to remove unchanged starting materials, dried and crystallized from isopropanol to yield 47.0 g. of 6,7-dimethoxy 2-[2-(3,4-dimethyl-benzoyl)-4-methyl-pentyl]- 1methyl1,2,3,4-tetrahydro-isoquinoline hydrochloride as a white solid of melting point 168 -169 C.

A suspension of 38.33 g. of 6,7-dimethoxy-2-[2-(3,4- dimethyl benzoyl) 4 methyl-pentyl]-l-methyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride and 2 g. of 5% palladium-on-carbon in 500 ml. of methanol was hydrogenated at room temperature and atmospheric pressure until the theoretical amount of hydrogen (0.084 mol) had been absorbed. The catalyst was then filtered oil and the filtrate evaporated under reduced pressure. The residue was crystallized from methanol/(ethyl acetate) to yield 32.4 g. of 6,7-dimethoxy-2-[2-(3,4-dirnethyl-a-hydroxybenzyl) 4 methyl-pentyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride as a white crystalline solid of melting point 231-232 C.

10.0 g. of 6,7-dimethoxy-2-[2-(3,4-dimethyl-a-hydroxybenzyl) 4 methyl-pentyl]-l-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and a mixture of 0.5 ml. of 70% perchloric acid and ml. of acetic anhydride were warmed on a water-bath for 0.5 hour. The resulting solution was allowed to stand at room temperature for 4 days, then poured on to ice, made basic with aqueous sodium hydroxide solution while cooling with ice and extracted three times with dichloro-methane. The combined dichloro-methane extracts were washed with water, dried over anhydrous sodium sulphate, filtered and the filtrate evaporated under reduced pressure. The oily residue was dissolved in ethanol, treated with ethanolic hydrogen chloride and evaporated under reduced pressure. The viscous residue was crystallized from ethyl acetate to yield 8.0 g. of 2 [2 (a acetoxy-3,4-dimethyl-benzyl)-4-methylpentyl] 6,7 dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride in the form of white crystals of melting point 182184 C.

EXAMPLE 2 Reaction of the free base of 6,7-dimethoxy-2-[2-(3,4 dimethyl a hydroxy-benzyl)-4methyl-pentyl]-l-methyl-1,2,3,4-tetrahydro-isoquinoline, with propionyl chloride in the presence of triethylamine gave 2-[2-(a-propionoxy- 3,4 dimethyl benzyl)-4-methyl-pentyl]-6,7-dimethoxyl-methyl-1,2,3,4-tetrahydroisoquinoline, which was isolated in the form of its hydrochloride of melting point 171-173 C. (from ethyl acetate).

EXAMPLE 3 (A) The preparation of the starting material 1,2 dimethyl 4-octauoyl-benzene was prepared from octanoyl chloride, aluminum chloride and ortho-xylene in dichloro-methane by a procedure analogous to that described in part A of Example 1.

7 (B) The process v.A mixture of 23.2 g. of 1,2-dimethyl-4-octanoyl-benzene, 24.4 g. of 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 4.5 g. of paraformalde hyde, 0.2 ml. of concentrated hydrochloricacid and 50 ml. of methylated spirits was heated under reflux for 72 hours, further quantities of paraformaldehyde (4.5 g. on each occasion) being added after 24 hours and 48 hours. After cooling, the resulting mixture was worked up to yield 11.4 g. of 6,7-dimethoxy-2-[2-(3,4-dimethyl-benzoyl)-octyl]-1-methyl-1,2,3,4-tetrahydro isoquinoline hydrochloride of melting point 170172 C. (from ethyl acetate).

A suspension of 4.9 g. of 6,7-dimethoxy-2-[2-(3,4-dimethylbenzoyl)-octyl] 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 1 g. of 5% palladium-ncarbon in 100 ml. of methanol was hydrogenated in the manner described in the second paragraph of part B of Example 1 and the resulting mixture was worked up to yield 3.8 g. of 6,7-dimethoxy-2-[2-(3,4-dimethyl-a-hydroxy-benzyD-octyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride of melting point 201 -203 C. (from isopropanol).

1.96 g. of 6,7-dimethoxy-2-[2-(3,4-dimethyl-a-hydroxybenzyl)-octyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride were heated with a mixture of 0.2 ml. of 70% perchloric acid and 25 ml. of acetic anhydride in a manner analogous to that desrcibed in the final paragraph of part B of Example 1 and the resulting mixture was worked up to yield 1.25 g. of 2-[2- (a-acetoxy-3,4-dimethyl-benzyl)-octyl]-6,7-dimethoxy 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride of melting point 174- 176 C. (from isopropanol).

EXAMPLE 4 (A) The preparation of the starting material 4-(2-cyclohexyl-acetyl)-1,2-dimethyl-benzene was prepared from 107 g. of 2-cyclohexyl-acetyl chloride, 94 g. of aluminum chloride and 70 g. of ortho-xylene in dichloromethane by a procedure analogous to that described in part A of Example 1.

(B) The process A mixture of 23.0 g. of 4-(2-cyclohexyl-acetyl)-1,2-di methylbenzene, 24.4 g. of 6,7-dimethoxy-1-methyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride, 4.5 g. of paraformaldehyde, 0.2 ml. of concentrated hydrochloric acid and 50 ml. of methylated spirits was heated under reflux for 72 hours, further quantities of paraformaldehyde (4.5 g. on .each occasion) being added after 24 and 48 hours. After cooling, the resulting mixture was worked up to yield 11.2 g. of 2-[2-cyclohexyl-3-(3,4-dimethylphenyl)- 3-oxo-propyl]-6,7-dimethoxy 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride of melting point 200- 201 C. (from ethanol).

A suspension of 4.86 g. of 2-[2-cyclohexyl-3-(3,4-dimethylphenyl)-3-oxo-propyl]-6,7-dimethoxy l methyl- 1,2,3,4-tetrahydro-isoquinoline hydrochloride and 1 g. of 5% palladium-on-carbon in 200 ml. of methanol was bydrogenated in the manner described in the second paragraph of part B of Example 1 and the resulting mixture was worked up to yield 2.6 g. of 2-[2-cyclohexyl-3-(3,4- dimethyl-phenyl)-3-hydroxy-propyl] 6,7 dimethoxy-lmethyl-1,2,3,4 tetrahydro-isoquinoline hydrochloride of melting point 225-22 6 C. [from methanol/(ethylacetate)].

2 g. of 2-[2-cyclohexyl-3-(3,4-dimethyl-phenyl)-3-hydroxy-propyl]-6,7-dimethoxy 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride were treated with a mixture of 25 ml. of acetic anhydride and 0.1 ml. of 70% perchloric acid in a manner analogous to that described in the final paragraph of part B of Example 1 and the resulting mixture was worked up to yield 1.1 g. of 2-[3- actoxy 2 cyclohexyl-3-(3,4 dimethyl-phenyl)-propyl]- 6,7-dimethoxy-1-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride of melting point 19019l C. (from isopropanol/ ether) EXAMPLE 5 (A) The preparation of the starting material 2-butyryl-5,6,7,S-tetrahydro-naphthalene (boiling point -123 C./ 0.7 mm.) was prepared by procedure analogous to that described in part A of Example 1 from 26 g. of butyryl chloride, 37.2 g. of aluminum chloride and 39.5 g.- of Tetralin in 200 ml. of dichloro-rnethane (B) The process A mixture of 20.2 g. of 2-butyryl-5,6,7,S-tetrahydronaphthalene, 24.4 g. of 6,7-dimethoxy-1-methyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride and 4.5 g. of paraformaldehyde was heated at reflux for 72 hoursin 50 ml. of ethanol containing 0.2 ml. of concentrated hydrochloric acid. Further quantities of paraformaldehyde (4.5 g. each time) were added to the mixture after 24 hours and 48 hours. The mixture was worked up in the manner described in the first paragraph of part B of Example 1 to yield 20.1 g. of 2-[2-ethyl-3-[5,6,7,8-tetrahydro-naphthyl-(2) ]-3-oxo-propyl]-6,7-dimethoxy l-methyl-l,2,3,4 tetrahydro-isoquinoline hydrochloride as a white solid of melting point 197198 C.

1 g. of sodium borohydride was added to a solution of 2.3 g. of 2-[2-ethyl-3-[5,6,7,S-tetrahydro-naphthyl-(2)]- 3-oxo-propyl]-6,7-dimethoxy 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride in 50 ml. of ethanol and 5 ml. of 2 N sodium hydroxide. The mixture was stirred for 6 hours, evaporated under reduced pressure to remove the ethanol and the residue was partitioned between dichloro-methane and water. The organic phase was separated, washed with water and dried over anhydrous sodium sulphate. The sodium sulphate was removed by filtration, the filtrate evaporated to dryness and the residue dissolved in ethanol. The ethanolic solution was then treated with ethanolic hydrogen chloride and the resulting solution was evaporated under reduced pressure to give a white solid which was recrystallized from ethyl acetate to yield 2-[2-ethyl-3-[5,6,7,S-tetrahydro-naphthyl- 2) -3-hydroxy-propyl] -6,7-dimethoxy 1-methyl-1,2,3 ,4- tetrahydro-isoquinoline hydrochloride of melting point 178-182 C.

EXAMPLE 6 (A) The preparation of the starting material 3,4' dimethyl-propiophenone (boiling point=l35- l40/15 mm.) was prepared from propionyl chloride, aluminum chloride and ortho-xyleue in dicbloro-methane by a procedure analogous to that described in part A of Example 1.

(B) The process Reaction of 3',4-dimethyl-propiophenone with 6,7-dimethoxy-I-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride and paraformaldehyde in a manner analogous to that described in the first paragraph of part B of Example 1 gave =6,7-dirnethoxy-2-[2-(3,4-dimethyl-benzoyl)- propyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline which was isolated in the form of its hydrochloride of melting point 183 C. (from isopropanol).

:Hydrogenation of 6,7-dimethoxy-2-[2-(3,4-dimethylbenzoyl)-propyl] 1 methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride in the presence of platinum oxide in a manner analogous to that described in the second paragraph of part B of Example 1 gave 6,7-dimethoxy-2-[2- (3,4 dimethyl-a-hydroxy-benzyl)-propyl] -1-methyl-1,2,3, 4-tetrahydro-isoquinoline, which was isolated in the form of its hydrochloride of melting point 210212 C. (from methanol).

Acetylation of 6,7-dimethoxy-2-[2-(3,4-dimethyl-a-hydroxy-benzyl)-propyl]-l-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride with acetic anhydride in a manner analogous to that described in the final paragraph of part B of Example 1 gave 2-[2-(a-acetoxy 3,4-dimethylbenzyl)-propyl]-6,7-dimethxy-1-methyl l,2,3,4 tetrahydro-isoquinoline which was isolated in the form of its hydrochloride and crystallized from ethyl acetate to give a white crystalline solid of melting point 157-160 C.

EXAMPLE 7 (A) The preparation of the starting material 1,2-dimethyl-4-hexanoyl-benzene (boiling point: 167 168 C./9 mm.) was prepared from caproyl chloride, aluminum chloride and ortho-xylene in dichloro-methane by a procedure analogous to that described in part A of Example 1.

(B) The process Reaction of 1,2-dimethyl-4-hexanoyl-bnezene with 6,7- dimethoxy-l-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride and paraformaldehyde in a manner analogous to that described in the first paragraph of part B of Example 1 gave 6,7-dimethoxy-2-[2-(3,4-dimethyl-benzoyl)- hexyl]-l-methyl-l,2,3,4-tetrahydro-isoquinoline which was isolated in the form of its hydrochloride melting at 184- 186 C. after recrystallization from methanol/ (ethyl acctate).

Hydrogenation of 6,7 dimethoxy-2-[2-(3,4-dimethylbenzoyl)-hexyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride in the presence of palladium-on-earbon in a manner analogous to that described in the second paragraph of part B of Example 1 gave 6,7-dimethoxy- 2-[2 (3,4-dimethyl-a-hydroxy-benzyl)-hexyl]l-methyl- 1,2,3,4-tetrahydro-isoquinoline in the form of its hydrochloride melting at 247-248 C. after recrystallization from methanol/ (ethyl acetate).

Acetylation of 6,7-dimethoxy-2-[2-(3,4-dimethyl-u-hydroxybenzyl)-hexyl]-lmethyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride in a manner analogous to that described in the final paragraph of part B of Example 1 gave 2- [2- a-acetoxy-3,4-dimethy1-benzyl -hexyl] 6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydro-isoquinoline which was isolated in the form of its hydrochloride and crystallized from methanol/ (ethyl acetate) to give a crystalline solid of melting point 158-160 C.

EXAMPLE 8 (A) The preparation of the starting material 1,2-dimethyl 4 isovaleryl-benzene (boiling point: 150160 C./15 mm.) was prepared from isovaleryl chloride, aluminum chloride, and ortho-xylene in dichloromethane by a procedure analogous to that described in part A of Example 1.

(B) The process Reaction of 1,Z-dimethyl-4-isovaleryl-benzene with 6,7- dimethoxy-l-methyl l,2,3,4 tetrahydro-isoquinoline hydrochloride and paraformaldehyde in a manner analogous to that described in the first paragraph of part B of Example 1 gave 6,7-dimethoxy-2-[2-(3,4-dimethyl-benzoyl)-3-methyl-butyl]-l-methyl 1,2,3,4 tetrahydro-isoquinoline which was isolated in the form of its hydrochloride melting at 213-215 after recrystallization from methanol/ (ethyl acetate).

Hydrogenation of 6,7-dimethoxy-2-[2-(3,4-dimethylbenzoyl)-3-methyl-butyl]-1-methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride in the presence of palladiumon-carbon in a manner analogous to that described in the second paragraph of part B of Example 1 gave 6,7-dimethoxy-2-[2-(3,4-dimethyl-a-hydroxy-benzyl) 3 methyl-butyl]-1-methyl-l,2,3,4-tetrahydroisoquinoline in the form of its hydrochloride melting at 240-241 C. after recrystallization from methanol/ (ethyl acetate).

Acetylation of 6,7-dimethoxy-2-[Z-(BA-dimethyI-u-hydroxy-benzyl)-3-methyl-butyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride in a manner analogous to that described in the final paragraph part B of Example 1 gave 2 [2-(a-acetoxy-3,4-dimethyl-benzyl)-3-methylbutyl]-6,7-dimethoxy-1-methyl 1,2,3,4 tetrahydro-isoquinoline which was isolated in the form of its hydrochl0- ride of melting point 219-220 C. (from methanol).

EXAMPLE 9 (A) The preparation of the starting material 5-isocaproyl-indane (boiling point=137-140 C./0.1 mm.) was prepared from isocaproyl chloride, aluminum chloride and indane in dichloro-methane by a procedure analogous to that described in part A of Example 1.

(B) The process Reaction of S-isocaproyl-indane with 6,7-dimethoxy-1- methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride and paraformaldehyde in a manner analogous to that described in the first paragraph of part B of Example 1 gave 6,7 dimethoxy-2-[Z-(S-indanecarbonyl)-4-methylpentyl]-1-methyl 1,2,3,4 tetrahydro-isoquinoline which was isolated in the form of its hydrochloride of melting point l63-164 C. (from isopropanol).

Hydrogenation of 6,7 dimethoxy-2-[Z-(S-indanecarbonyl)-4-methyl-pentyl]-l-methyl 1,2,3,4 tetrahydroisoquinoline hydrochloride in the presence of palladiumon-carbon gave 6,7 dimethoxy-2-[3-hydroxy-3-(5-indanyl)-2-isobutyl-propyl]-1-methyl 1,2,3,4 tetrahydroisoquinoline in the form of its hydrochloride melting at 239-240 C. after recrystallization from methanol/ (ethyl acetate).

EXAMPLE 10 Reaction of 1,2-dimethyl-4-isocaproyl-benzene with 6,7 dimethoxy 1 methyl 1,2,3,4-tetrahydroisoquinoline hydrochloride and paraformaldehyde in a manner analogous to that described in the first paragraph of part B of Example 1 gave (+)-6,7-dimethoxy-2-[2- (3,4 dimethyl-benzoyl) 4 methyl-pentyl1-1-methyl- 1,2,3,4-tetrahydro-isoquinoline which was isolated in the form of its hydrochloride; melting point==128-l29 C., [a] =+20.2 (c.=0.5 in methanol).

Hydrogenation of 6,7 dimethoxy-2-[2-(3,4-dimethyl-benzoyl) 4 methyl-pentyl] 1 methyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride in the presence of palladium-on-carbon in a manner analogous to that described in the second paragraph of part B of Example 1 gave 6,7 dimethoxy 2 [2-(3,4-dimethyl-ahydroxy-benzyl) 4 methyl-pentyl] 1-methyl-1,2,3,4- tetrahydro-isoquinoline as its hydrochloride of melting point 230231 C.; [a] (04:70.5 in

methanol) EXAMPLE 11 The following examples illustrate pharmaceutical preparations containing the tetrahydro-isoquinoline derivatives provided by the invention:

Part A 15 g. of 2 [2 (u-acetoxy-3,4-dimethyl-benzyl)-octyl]- 6,7 dimethoxy 1 methyl 1,2,3,4 tetrahydro-isoquinoline hydrochloride, 102 g. of corn starch, 30 g. of hydrated silica and 3 g. of magnesium silicate were thoroughly mixed and the mass obtained was pressed into tablets each weighing mg.

Part B 3 g. of 2 [2 (a-acetoxy-3,4-dimethy1-benzyl)-octyl]- 6,7 dimethoxy 1 methyl 1,2,3,4-tetrahydro-isoquinoline hydrochloride, 44 g. of lactose, 48 g. of corn starch and 5 g. of talc were thoroughly mixed and the mass obtained was pressed into tablets each weighing 100 mg.

1 1 We claim: 1. A compound of the formula HaC--0 and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein R and R each represent methyl.

3. The compound of claim 2 of the formula 6,7-dimethoxy 2 [2 (3,4 dimethyl-a-hydroxy-benzyl)-4- methyl-pentyl] 1 methyl 1,2,3,4 tetrahydro-isoquinoline.

4. The compound of claim 2 of the formula 6,7-dimethoxy-2-[2-(a-acetoxy 3,4 dimethyl-benzyl)-4-methylpentyl]-1-methyl-l,2,3,4-tetrahydro-isoquinoline.

5. The compound of claim 2 of the formula 6,7-di- 12 methoxy 2 [2 (3,4 dimethyl-a-hydroxy-benzyl)- octyl]-l-methyl-l,2,3,4-tetrahydro-isoquinoline.

6. The compound of claim 2 of the formula 2-[2-(azacetoxy 3,4 dimethyl-benzyl)-octyl] 6,7 dimethoxyl-methyl-1,2,3,4-tetrahydro-isoquinoline.

7. The compound of claim 2 of the formula 2-[2-cyclohexyl 3 (3,4 dimethyl-phenyl) 3 hydroxy-propyl]- 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline.

8. The compound of claim 2 of the formula 2-[3- acetoxy 2 cyclohexyl 3 (3,4 dimethylphenyl)- propyl] 6,7 dimethoxy 1 methyl 1,2,3,4-tetrahydroisoquinoline.

9. The compound of claim 1 of the formula 2-[2-ethyl- 3 [5,6,7,8 tetrahydro-naphthyl-(Z) ]-3-hydroxy-propyl]- 6,7-dimethoxy-1-methy1-1,2,3,4-tetrahydro-isoquino1ine.

References Cited UNITED STATES PATENTS 3,146,266 8/1964 Besendorf et a1. 260-289 R 3,238,212 3/1966 Brossi 260287 R 3,459,704 6/ 1969 Osbond et a1 260289 R 3,609,154 9/1971 Fothergill 260-289 R DONALD G. DAUS, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 12,133

DATED May 21, 1974 |NV ENTOR(S) John Mervyn Osbond and Graham Alwyn Fothergill It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, after 'Ser. No. 203,100" insert Foreign Application Priority Data November 30, 1970 Great Britain Signed and Sealed this A lies I:

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner ojlarenls and Trademarks 

